This invention relates to certain novel 5-phenyl-2-furan esters and amides and the novel use of these and related compounds as antiepileptic agents.
Antiepileptic agents are used to treat seizure disorders. Approximately 2.5 million of all Americans have epilepsy. Epilepsy often begins in childhood, with three quarters of the patients having their first seizure before the age of 18. Two hundred thousand Americans have epileptic seizures more than once a month. Most epileptic patients are dependent on drugs to control seizures, but therapy is often inadequate. For certain types of seizures there are no specific drugs available.
The modern history of antiepileptic drugs marketed in the United States began in 1912 with the introduction of phenobarbital, a synthetic sedative-hypnotic drug which was shown to reduce seizure frequency. Since the barbituric acid molecule is easily modified, many analogs of phenobarbital were synthesized and marketed for antiepileptic activity. Antiepileptic drug development then entered a dormant period lasting for twelve years, from 1961 to 1973, during which the only new drug of interest was diazepam, an adjunctive drug used mostly in status epilepticus.
In 1968, the Epilepsy Branch of the National Institute of Neurological and Communicative Disorders attempted to reverse the decline in antiepileptic drug development by conducting controlled clinical trials of several drugs that needed proof of efficacy. The resulting data eventually supported new drug applications for carbamazepine in 1974, clonazepam in 1975 and valproic acid in 1978.
Many patients with common types of seizures and most of those with rare types fail to respond to available drugs and/or suffer adverse side effects. The currently available antiepileptic drugs have many adverse side effects. They include cardiovascular collapse, central nervous system depression, aplastic anemia, congestive heart failure, visual hallucinations, liver damage, impaired cognition, ataxia, personality changes, psychosis, aggressive behavior, nausea, dizziness and sedative effects. For those patients whose seizures are controlled with currently available therapy, a new drug may allow a reduction in the adverse side effects. It has been discovered that certain 5-phenyl-2-furan esters and amides have antiepileptic activity. These compounds are potentially less toxic and/or have greater efficacy than current agents used clinically as antiepileptic agents.
A number of phenyl furans are described in the literature. However, these compounds have never been suggested to have antiepileptic activity. For example, U.S. Pat. No. 3,856,825 issued to Wright et al. on Dec. 24, 1974, discloses a series of 3-diethylamino-2,2-dimethylpropyl 5-(substituted phenyl)-2-furoates that possess pharmacological properties, particularly being useful as antispasmodics. U.S. Pat. No. 4,162,257 issued to Pelosi and Yu on July 24, 1979, discloses N,N-dimethyl-5-phenyl-2-furamides said to be useful as anti-inflammatory agents. Oleinik, A. F. et al., "Synthesis and Tuberculostatic Activity of 5-Arylpyromucic Acid Derivatives", Pharmaceutic Chemical Journal, Vol. 10, No. 4 (April, 1976), pages 463-465, discloses certain 5-phenyl-2-furans said to have bacteriostatic activity.